Using machine learning with passive wearable sensors to pilot the detection of eating disorder behaviors in everyday life.

BACKGROUND: Eating disorders (ED) are serious psychiatric disorders, taking a life every 52 minutes, with high relapse. There are currently no support or effective intervention therapeutics for individuals with an ED in their everyday life. The aim of this study is to build idiographic machine learning (ML) models to evaluate the performance of physiological recordings to detect individual ED behaviors in naturalistic settings. METHODS: From an ongoing study (Final N = 120), we piloted the ability for ML to detect an individual's ED behavioral episodes (e.g. purging) from physiological data in six individuals diagnosed with an ED, all of whom endorsed purging. Participants wore an ambulatory monitor for 30 days and tapped a button to denote ED behavioral episodes. We built idiographic (N = 1) logistic regression classifiers (LRC) ML trained models to identify onset of episodes (~600 windows) v. baseline (~571 windows) physiology (Heart Rate, Electrodermal Activity, and Temperature). RESULTS: Using physiological data, ML LRC accurately classified on average 91% of cases, with 92% specificity and 90% sensitivity. CONCLUSIONS: This evidence suggests the ability to build idiographic ML models that detect ED behaviors from physiological indices within everyday life with a high level of accuracy. The novel use of ML with wearable sensors to detect physiological patterns of ED behavior pre-onset can lead to just-in-time clinical interventions to disrupt problematic behaviors and promote ED recovery.

Chloroplastic pentatricopeptide repeat proteins (PPR) in albino plantlets of Agave angustifolia Haw. reveal unexpected behavior.

BACKGROUND: Pentatricopeptide repeat (PPR) proteins play an essential role in the post-transcriptional regulation of genes in plastid genomes. Although important advances have been made in understanding the functions of these genes, there is little information available on chloroplastic PPR genes in non-model plants and less in plants without chloroplasts. In the present study, a comprehensive and multifactorial bioinformatic strategy was applied to search for putative PPR genes in the foliar and meristematic tissues of green and albino plantlets of the non-model plant Agave angustifolia Haw. RESULTS: A total of 1581 PPR transcripts were identified, of which 282 were chloroplastic. Leaf tissue in the albino plantlets showed the highest levels of expression of chloroplastic PPRs. The search for hypothetical targets of 12 PPR sequences in the chloroplast genes of A. angustifolia revealed their action on transcripts related to ribosomes and translation, photosystems, ATP synthase, plastid-encoded RNA polymerase and RuBisCO. CONCLUSIONS: Our results suggest that the expression of PPR genes depends on the state of cell differentiation and plastid development. In the case of the albino leaf tissue, which lacks functional chloroplasts, it is possible that anterograde and retrograde signaling networks are severely compromised, leading to a compensatory anterograde response characterized by an increase in the expression of PPR genes.

SNAI1-expressing fibroblasts and derived-extracellular matrix as mediators of drug resistance in colorectal cancer patients.

Resistance to antitumor treatments is one of the most important problems faced by clinicians in the management of colorectal cancer (CRC) patients. Cancer-Associated Fibroblasts (CAFs) are the main producers and remodelers of the extracellular matrix (ECM), which is directly involved in drug resistance mechanisms. Primary Normal Fibroblasts (NFs) and CAFs and cell lines (fibroblasts and tumor cells), were used to generate ECM and to identify its role in the oxaliplatin and cetuximab chemoresistance processes of CRC cells mediated by SNAI1-expressing fibroblasts. Matrices generated by Snai1 KO MEFs (Knockout Mouse Embryonic Fibroblasts) confer less resistance on oxaliplatin and cetuximab than wild-type MEF-derived matrices. Similarly, matrices derived from CAFs cause greater survival of colorectal cancer cells than NF-derived matrices, in a similar way to Snai1 expression levels. In addition, Snail1 expression in fibroblasts regulates drug resistance and metabolism gene expression in tumor cells mediated by ECM. Finally, a series of 531 patients (TCGA) with CRC was used to assess the role of SNAI1 expression in patients' prognosis indicating an association between tumor SNAI1 expression and overall survival in colon cancer patients but not in rectal cancer patients. SNAI1 expression in CRC cancer patients, together with in vitro experimentation, suggests the possible use of SNAI1 expression in tumor-associated fibroblasts as a predictive biomarker of response to oxaliplatin and cetuximab treatments in patients with CRC.

Emerging alternatives against Clostridioides difficile infection.

Clostridioides difficile infection (CDI) is a significant worry within healthcare institutions and the community. It is one of the leading agents causing severe diarrhea worldwide. Effective management is critical since the morbidity and mortality attributed to CDI have increased exponentially over the past 20 years. Currently, antibiotics are the standard treatment for primary C. difficile infection, but at the same time, they are associated with disease relapse and increased drug resistance. CDI's high recurrence rates, spore generation, and antimicrobial resistance are currently significant challenges that urge the development of new options to combat this infection. This review describes up-and-coming alternatives and how they can mitigate the challenges associated with CDI. Here we have discussed the advantages and challenges of current and experimental alternatives against CDI.

Significant differences in access to tests and treatments for multiple myeloma between public and private systems in Latin America. Results of a Latin American survey. GELAMM (Grupo de Estudio Latino Americano de Mieloma Múltiple).

The incidence of multiple myeloma (MM) has increased in the last 20 years, particularly in middle and low-middle income countries. Access to diagnostic and prognostic tests and the availability of effective care is highly variable globally. Latin America represents 10% of the world population, distributed in countries of varied size, population, and socio-economic development. In the last decade, great improvements have been made in the diagnosis and treatment of MM. Applying these advances in real life is a challenge in our region. Local data regarding MM standards of care and outcomes are limited. A survey was carried out among hematologists from 15 Latin American countries to describe access to MM diagnostic and prognostic tests and the availability of effective care options. This study provides real-world data for MM in our region, highlighting striking differences between public and private access to essential analyses and therapeutic options.

Phase I dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer.

BACKGROUND: Copanlisib is a pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant PI3K-α/δ activity that has demonstrated clinical activity and manageable safety when administered as monotherapy in a phase II study. Combination therapy may overcome compensatory signalling that could occur with PI3K pathway inhibition, resulting in enhanced inhibitory activity, and preclinical studies of copanlisib with gemcitabine have demonstrated potent anti-tumour activity in vivo. METHODS: A phase I, open-label, dose-escalation study to evaluate the safety, tolerability and recommended phase II dose (RP2D) of copanlisib with gemcitabine or with cisplatin plus gemcitabine (CisGem) in patients with advanced malignancies, including an expansion cohort in patients with biliary tract cancer (BTC) at the RP2D of copanlisib plus CisGem. Copanlisib and gemcitabine were administered on days 1, 8 and 15 of a 28-day cycle; maximum tolerated dose (MTD) and RP2D of copanlisib were determined. Copanlisib plus CisGem was administered on days 1 and 8 of a 21-day cycle; pharmacokinetics and biomarkers were assessed. RESULTS: Fifty patients received treatment as follows: dose-escalation cohorts, n=16; copanlisib plus CisGem cohort, n=14; and BTC expansion cohort, n=20. Copanlisib 0.8 mg kg-1 plus gemcitabine was the MTD and RP2D for both combinations. Common treatment-emergent adverse events included nausea (86%), hyperglycaemia (80%) and decreased platelet count (80%). Copanlisib exposure displayed a dose-proportional increase. No differences were observed upon co-administration of CisGem. Response rates were as follows: copanlisib plus gemcitabine, 6.3% (one partial response in a patient with peritoneal carcinoma); copanlisib plus CisGem, 12% (one complete response and three partial responses all in patients with BTC (response rate 17.4% in patients with BTC)). Mutations were detected in PIK3CA (1 out of 43), KRAS (10 out of 43) and BRAF (2 out of 22), with phosphate and tensin homologue protein loss in 41% (12 out of 29). CONCLUSIONS: Copanlisib plus CisGem demonstrated a manageable safety profile, favourable pharmacokinetics, and potentially promising clinical response.

Oxygen uptake rate in alginate producer (algU+) and nonproducer (algU-) strains of Azotobacter vinelandii under nitrogen-fixation conditions.

AIMS: The sigma E (AlgU) in Azotobacter vinelandii has been shown to control the expression of cydR gene, a repressor of genes of the alternative respiratory chain, and alginate has been considered a barrier for oxygen diffusion. Therefore, the aim of the present study was to compare the respiratory activity of an alginate nonproducing strain, lacking the sigma factor E (algU-), and polymer-producing strains (algU+) of A. vinelandii under diazotrophic conditions at different aeration conditions. METHODS AND RESULTS: Our results reveal that under diazotrophic and high aeration conditions, A. vinelandii strain OP (algU-) had a specific oxygen consumption rate higher (30 and 54%) than those observed in the OP algU+-complemented strain, named OPAlgU+, and the ATCC 9046 respectively. However, the specific growth rate and biomass yields (based on oxygen and sucrose) were lower for OP cultivations as compared to the algU+ strains. These differences were partially explained by an increase in 1·5-fold of cydA relative expression in the OP strain, as compared to that obtained in the isogenic OPAlgU+ strain. CONCLUSIONS: Overall, our results confirm the important role of algU gene on the regulation of respiratory metabolism under diazotrophic growth when A. vinelandii is exposed to high aeration. SIGNIFICANCE AND IMPACT OF THE STUDY: This study highlights the role of AlgU to control respiration of A. vinelandii when exposed to diazotrophy.

Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma.

BACKGROUND: Copanlisib is a pan-class I phosphatidylinositol 3-kinase inhibitor with predominant activity against the α- and δ-isoforms. PATIENTS AND METHODS: This phase II study evaluated the response rate of copanlisib administered intravenously on days 1, 8, and 15 of a 28-day cycle, in patients with indolent or aggressive malignant lymphoma. Archival tumor tissues were used for immunohistochemistry, gene-expression profiling, and mutation analysis. RESULTS: Thirty-three patients with indolent lymphoma and 51 with aggressive lymphoma received copanlisib. Follicular lymphoma (48.5%) and peripheral T-cell lymphoma (33.3%) were the most common histologic subtypes. Most patients (78.6%) had received prior rituximab and 54.8% were rituximab-refractory. Median duration of treatment was 23 and 8 weeks in the indolent and aggressive cohorts, respectively (overall range 2-138). Eighty patients were evaluated for efficacy. The objective response rate was 43.7% (14/32) in the indolent cohort and 27.1% (13/48) in the aggressive cohort; median progression-free survival was 294 days (range 0-874) and 70 days (range 0-897), respectively; median duration of response was 390 days (range 0-825) and 166 days (range 0-786), respectively. Common adverse events included hyperglycemia (57.1%; grade ≥3, 23.8%), hypertension (54.8%; grade ≥3, 40.5%), and diarrhea (40.5%; grade ≥3, 4.8%), all generally manageable. Neutropenia occurred in 28.6% of patients (grade 4, 11.9%). Molecular analyses showed enhanced antitumor activity in tumors with upregulated phosphatidylinositol 3-kinase pathway gene expression. CONCLUSION: Intravenous copanlisib demonstrated promising efficacy and manageable toxicity in heavily pretreated patients with various subtypes of indolent and aggressive malignant lymphoma. Subtype-specific studies of copanlisib in patients with follicular, peripheral T-cell, and mantle cell lymphomas are ongoing. This trial is registered with ClinicalTrials.gov number NCT01660451 (Part A).

First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin's lymphomas.

BACKGROUND: To evaluate the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of copanlisib, a phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors or non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Phase I dose-escalation study including patients with advanced solid tumors or NHL, and a cohort of patients with type 2 diabetes mellitus. Patients received three weekly intravenous infusions of copanlisib per 28-day cycle over the dose range 0.1-1.2 mg/kg. Plasma copanlisib levels were analyzed for pharmacokinetics. Biomarker analysis included PIK3CA, KRAS, BRAF, and PTEN mutational status and PTEN immunohistochemistry. Whole-body [(18)F]-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) was carried out at baseline and following the first dose to assess early pharmacodynamic effects. Plasma glucose and insulin levels were evaluated serially. RESULTS: Fifty-seven patients received treatment. The MTD was 0.8 mg/kg copanlisib. The most frequent treatment-related adverse events were nausea and transient hyperglycemia. Copanlisib exposure was dose-proportional with no accumulation; peak exposure positively correlated with transient hyperglycemia post-infusion. Sixteen of 20 patients treated at the MTD had reduced (18)FDG-PET uptake; 7 (33%) had a reduction >25%. One patient achieved a complete response (CR; endometrial carcinoma exhibiting both PIK3CA and PTEN mutations and complete PTEN loss) and two had a partial response (PR; both metastatic breast cancer). Among the nine NHL patients, all six with follicular lymphoma (FL) responded (one CR and five PRs) and one patient with diffuse large B-cell lymphoma had a PR by investigator assessment; two patients with FL who achieved CR (per post hoc independent radiologic review) were on treatment >3 years. CONCLUSION: Copanlisib, dosed intermittently on days 1, 8, and 15 of a 28-day cycle, was well tolerated and the MTD was determined to be 0.8 mg/kg. Copanlisib exhibited dose-proportional pharmacokinetics and promising anti-tumor activity, particularly in patients with NHL. CLINICALTRIALSGOV: NCT00962611; https://clinicaltrials.gov/ct2/show/NCT00962611.

A chimeric cyclic interferon-α2b peptide induces apoptosis by sequential activation of phosphatidylinositol 3-kinase, protein kinase Cδ and p38 MAP kinase.

We have previously demonstrated that tyrosine phosphorylation of STAT1/3 and p38 mitogen-activated protein kinase (p38 MAPK) activation are involved in the apoptotic response triggered by a chimeric cyclic peptide of the interferon-α2b (IFN-α2b) in WISH cells. Since the peptide also induced serine phosphorylation of STAT proteins, in the present study we examined the kinase involved in serine STAT1 phosphorylation and the signaling effectors acting upstream such activation. We first found that p38 MAPK is involved in serine STAT1 phosphorylation, since a reduction of phophoserine-STAT1 levels was evident after incubating WISH cells with cyclic peptide in the presence of a p38 pharmacological inhibitor or a dominant-negative p38 mutant. Next, we demonstrated that the peptide induced activation of protein kinase Cδ (PKCδ). Based on this finding, the role of this kinase was then evaluated. After incubating WISH cells with a PKCδ inhibitor or after decreasing PKCδ expression levels by RNA interference, both peptide-induced serine STAT1 and p38 phosphorylation levels were significantly decreased, indicating that PKCδ functions as an upstream regulator of p38. We also showed that PKCδ and p38 activation stimulated by the peptide was inhibited by a specific pharmacological inhibitor of phosphatidylinositol 3-kinase (PI3K) or by a dominant-negative p85 PI3K-regulatory subunit, suggesting that PI3K is upstream in the signaling cascade. In addition, the role of PI3K and PKCδ in cyclic peptide-induced apoptosis was examined. Both signaling effectors were found to regulate the antiproliferative activity and the apoptotic response triggered by the cyclic peptide in WISH cells. In conclusion, we herein demonstrated that STAT1 serine phosphorylation is mediated by the sequential activation of PI3K, PKCδ and p38 MAPK. This signaling cascade contributes to the antitumor effect induced by the chimeric IFN-α2b cyclic peptide in WISH cells.

Genetic analysis in APC, KRAS, and TP53 in patients with stomach and colon cancer.

BACKGROUND: Stomach cancer (SC) and colorectal cancer (CRC) present with high rates of incidence and mortality in the worldwide population. These 2 tumors are characterized by great genetic heterogeneity. Up to now, there have been no molecular studies that analyze the mutations in the APC, KRAS, and TP53 genes in the Colombian/Latin American population. OBJECTIVES: To analyze mutations in the APC, KRAS, and TP53 genes through direct sequencing in 59 patients with SC and CRC. PATIENTS AND METHODS: Twenty-nine patients with SC and 30 with CRC were studied. An analysis of the mutations of the 3 genes was carried out using polymerase chain reaction and direct sequencing techniques. RESULTS: A 30.5% total mutation frequency was found. The most frequently mutated gene was APC (15.3%), followed by KRAS (10.1%) and TP53 (5.1%). The CRC samples had a mutation frequency of 46.7% and it was 13.3% in the SC samples (P=.006). No mutations occurred simultaneously in the 3 genes. Mutations in 2 genes were found in only 6 tumor samples (10%). There was also a high frequency of polymorphisms in both types of cancer, the most common of which was the rs41115 polymorphism, located on the APC gene. CONCLUSION: The APC, KRAS, and TP53 gene mutations were more common in CRC than in SC. Our results suggest the existence of different genetic pathways in the carcinogenesis of SC and CRC and they also reveal a particular mutation frequency in the Colombian patients studied; this could be influenced by factors related to the environment, ethnicity, and lifestyle of this population.

Sarcopenia measured by tomography as a predictor of morbidity and mortality in thoracic surgery, a retrospective cohort study.

BACKGROUND: Sarcopenia has been identified as a risk factor for perioperative adverse events. Several studies have shown that tomographic assessment of muscle mass can be an appropriate indicator of sarcopenia associated with morbidity and mortality. The aim of the study was to determine the association between height-adjusted area of ​​the pectoral and erector spinae muscles (haPMA and haESA) and perioperative morbidity and mortality in thoracic surgery. METHODS: Retrospective cohort study. Measurement of muscle areas was performed by tomography. The outcomes were 30-day mortality and postoperative morbidity. The discriminative capacity of the muscle areas was evaluated with an analysis of ROC curves and the Youden index was used to establish a cut-off point. The raw morbidity and mortality risk was determined and adjusted for potential confounders. RESULTS: A total of 509 patients taken to thoracic surgery were included. The incidence of 30-day mortality was 7.3%. An association was found between muscle areas and 30-day mortality and pneumonia, with adequate discriminative power for mortality (AUC 0.68 for haPMA and 0.67 for haESA). An haPMA less than 10 and haESA less than 8.5 cm2/m2 were identified as a risk factor for 30-day mortality with an adjusted OR of 2.34 (95%CI 1.03-5.15) and 2.22 (95%CI 1.10-6.04) respectively. CONCLUSIONS: Sarcopenia, defined as low muscle area in the pectoral and erector spinae muscles, is associated with increased morbidity and mortality in patients undergoing thoracic surgery.

Influence of Application Modes on Increasing Bond Strength Longevity of Self-etching and Universal Adhesive Systems to Enamel.

The present study aimed to evaluate the influence of application mode on the short-term microshear bond strength longevity of self-etching and universal adhesive systems to enamel, the failure mode, and the resulting enamel surface micromorphology. Ninety enamel surfaces were obtained from sound third molars, planed, and randomly assigned to nine groups, according to the application mode and the adhesive system (n=10). There were three primer application modes: according to the manufacturer's recommended application time (control), using double the application time recommended for the primer and selective enamel etching. The adhesive systems used were: Clearfil SE Bond (Kuraray), FL-Bond II (SHOFU), and Futurabond U (Voco). At least two resin-bonded composite cylinders (Grandioso Light Flow, Voco) were placed on each enamel surface, and then evaluated for microshear bond strength at 24 hours and 180 days of storage in solution body fluid (SBF) at pH 7.4. Failure modes were evaluated with a stereoscopic microscope at 20× magnification. A micromorphological analysis of the enamel surface was performed under a scanning electron microscope at 5000× magnification before and after the treatments. Mixed models for repeated measures over time showed significant interaction among application modes, adhesive systems, and time periods (p=0.0331). The bond strength of FL-Bond II adhesive to enamel observed after performing selective enamel etching was significantly higher than that observed after applying the control treatment (p=0.0010) at both 24 hours and 180 days. However, no significant difference was observed between the application of this same adhesive at double the time recommended by the manufacturer and the other two application modes (p>0.05). There was also no significant difference in the microshear bond strength for the enamel treatments applied using Clearfil SE Bond and Futurabond U (p>0.05). A significant reduction in bond strength to enamel was observed at the 180-day storage time for all the adhesive systems when selective enamel etching was performed (p<0.0001). No significant association was observed between the adhesive system failure mode and the enamel treatments (p=0.1402 and p=0.7590 for 24 hours and 180 days, respectively). The most prevalent failure was the adhesive type.

E-consults between primary care and internal medicine: implementation, accessibility, benefits, and implications.

AIM: This work aims to evaluate whether electronic consultations (e-consults) are a clinically useful, safe tool for assessing patients between primary care and internal medicine. METHODS: This is a retrospective cohort study of all e-consults ordered by the Primary Care Department to the Internal Medicine Department between September 2019 and December 2023. The results of initial consultations, emergency department visits and subsequent admissions, and survival were assessed and complaints and claims filed were reviewed. RESULTS: A total of 11,434 e-consults were recorded (55.4% women) with a mean age of 62.1 (SD19.4) years and a wide range (15-102 years). The mean response time was 2.55 (SD 1.6) days. As a result of the e-consults, 5645 patients (49.4%) were given an in-person appointment. For the remaining 5789 (50.6%), a written response was provided. Among those given appointments, the time between the response and in-person appointment was less than five days (95% of cases). Compared to those not given appointments, in-person appointments were older (p < 0.0001), visited the emergency department more times (one month: p = 0.04; three months: p = 0.001), were admitted to the hospital more times (one month: p = 0.0001; three months: p = 0.0001), and had higher mortality at one year (12.7% vs. 9.8% p = 0.0001). In the Cox analysis, only in-person appointments (RR = 1.11; p = 0.04)) and age (RR = 1.09; p < 0.01) were independent factors of mortality. No complaints or claims of any kind were registered. CONCLUSIONS: These data suggest that e-consults are a clinically useful, safe tool for assessing patients referred from primary care to internal medicine departments.

[Assessment of blood eosinophil count in respiratory disease from primary care]. / Valoración del recuento sanguíneo de eosinófilos en la patología respiratoria desde atención primaria.

Most physicians in general, and family physicians in particular, are familiar with certain parameters when ordering a hematological study, such as hemoglobin (including hematocrit and its features), leukocytes (including lymphocytes) and platelets. Nevertheless, there are two values that we use to overlook which are eosinophils and basophils. Specifically, eosinophils have a tendency to increase with allergic pathology. This article focuses on this type of cells, helping to interpret the values obtained and highlighting their importance in two of the most frequent respiratory pathologies in primary care: asthma and COPD. In addition to observing how the increase or normality of these parameters condition the diagnosis, phenotype and even the treatment.

Long-Term Treatment with Alcaligenes faecalis A12C Improves Host Resistance to Pathogens in Septic Rats: Possible Contribution of Curdlan-Like Immune Trainer.

Curdlan, a ß-1,3/1,6-glucan found in Alcaligenes faecalis (A. faecalis) wall, activates innate and humoral immunity. The aim of this study is to evaluate whether pretreated rats with A. faecalis A12C could prevent sepsis disturbances and identify the immunomodulatory mechanisms involved. Experiments occurred in two stages: a survival study with 16 rats randomly divided into septic (SC) (n = 8) and septic pretreated (SA) (n = 8) groups and 45 rats divided into four groups: healthy (AGUSAN) (n = 9), septic (AGUIC) (n = 13), septic pretreated (AGUIA) (n = 14), and healthy pretreated (AGUSTO) (n = 9). Sepsis was induced by cecal ligation and puncture after 30 days of A. faecalis A12C pretreatment or without. SA group had a higher survival rate of 58% vs. 16% for SC group (P < 0.05). Overall, AGUIA showed better status than AGUIC (P < 0.01). Higher monocytosis was found in AGUIA and AGUSTO vs. AGUIC and AGUSAN, respectively (P < 0.05). A gradual increase in curdlan fecal concentration was observed in AGUIA during pretreatment. Fecal concentrations of Escherichia coli significantly decreased in AGUIA and AGUSTO. Bacterial load in urine, peritoneal lavage fluid (PLF), and bronchoalveolar lavage fluid (BALF) decreased (P < 0.05) in AGUIA vs. AGUIC. Finally, lower inflammation was observed in serum, BALF, and PLF, with reduced IL-6, IL-10, IL-1ß, and TNF-α, along with less damage in lungs and peritoneum in AGUIA vs. AGUIC. These findings suggest the connection between curdlan-produced by A. faecalis A12C-with the immune system and the reduction in severity of experimental sepsis.

Impact of multidrug resistance on Pseudomonas aeruginosa ventilator-associated pneumonia outcome: predictors of early and crude mortality.

The prevalence of multidrug-resistant (MDR) Pseudomonas aeruginosa has increased over the past decade and a significant rise in these isolates in ventilator-associated pneumonia (VAP) has been observed. However, the impact of MDR on VAP outcome has not been analysed in depth. We investigated the risk factors for early and crude mortality in a retrospective study of microbiologically and clinically documented VAP. Ninety-one VAP episodes in 83 patients were included, 31 caused by susceptible P. aeruginosa and 60 by MDR strains, of which 42 (70 %) were extensively drug-resistant (XDR) P. aeruginosa. Thirteen episodes concomitantly presented P. aeruginosa bacteraemia, in seven of which the origin was the respiratory tract. Whereas susceptible P. aeruginosa episodes were more likely than MDR episodes to receive adequate empirical (68 % vs. 30 %; p < 0.001) and definitive antimicrobial therapy (96 % vs. 50 %; p < 0.001), susceptible P. aeruginosa VAP presented a trend towards early mortality (29 % vs. 15 %; p = 0.06). A logistic regression model with early mortality as the dependent variable identified multiorgan dysfunction syndrome (MODS) [odds ratio (OR) 10.4; 95 % confidence interval (CI) 1.7-63.5; p = 0.01] and inadequate antibiotic therapy (OR 4.27; 95 % CI 0.98-18.4; p = 0.052) as independent risk factors for early mortality. A similar analysis identified MODS (OR 4.31; 95 % CI 1.14-16.2; p = 0.03) as the only independent predictor of crude mortality. The severity of acute illness clinical presentation was the main predictor of mortality. Despite adequate antibiotic therapy, susceptible P. aeruginosa seems to cause major early mortality. Although adequate therapy is essential to treat VAP, the severity of acute illness is a more important factor than drug resistance.

Analysis of exosome release and its prognostic value in human colorectal cancer.

A significant proportion of extracellular nucleic acids in plasma circulate highly protected in tumor-specific exosomes, but it is unclear how the release of exosomes is modulated in carcinogenesis. We quantified by cytometry exosomes in plasma of 91 colorectal cancer patients to evaluate their potential as a tumor indicator and their repercussions on diagnosis and prognosis. We examined the involvement of TSAP6, a TP53-regulated gene involved in the regulation of vesicular secretion, in levels of circulating exosomes in plasma of colorectal patients and in HCT116 TP53-(wild-type and null) human colorectal cancer cell lines. The fraction of exosomes in cancer patients was statistically higher than in healthy controls (mean rank » 53.93 vs. 24.35). High levels of exosomes in plasma of patients correlated with high levels of carcino-embryonic antigen (P » 0.029) and with poorly differentiated tumors (P » 0.039) and tended to have shorter overall survival than patients with low levels (P » 0.056). Release of exosomes did not correlate with TSAP6 expression; and regulation of TSAP6 by TP53 was not shown either in tumor samples or in HCT116 cell lines. Although it was not suggested that the TP53/TSAP6 pathway regulates the release of exosomes into the plasma of colorectal cancer patients, the level of circulating exosomes may be used as a tumor indicator, because it correlates with poor prognosis parameters and shorter survival.